tbuckley/cabot-search huggingface dataset:
Early Clearance of Plasma <i>Epidermal Growth Factor Receptor</i> Mutations as a Predictor of Outcome on Osimertinib in Advanced Non–Small Cell Lung Cancer; Exploratory Analysis from AURA3 and FLAURA
Authors: Jhanelle E. Gray, Myung-Ju Ahn, Geoffrey R. Oxnard, Frances A. Shepherd, Fumio Imamura, Ying Cheng, Isamu Okamoto, Byoung Chul Cho, Meng-Chih Lin, Yi-Long Wu, Margarita Majem, Oliver Gautschi, Michael Boyer, Krishna C. Bulusu, Aleksandra Markovets, J. Carl Barrett, Rachel Hodge, Astrid McKeown, Ryan J. Hartmaier, Juliann Chmielecki, Vassiliki A. Papadimitrakopoulou, Suresh S. Ramalingam
Journal: Clinical Cancer Research (2023)

Plasma circulating tumor DNA (ctDNA) analysis is used for genotyping advanced non-small cell lung cancer (NSCLC); monitoring dynamic ctDNA changes may be used to predict outcomes.This was a retrospective, exploratory analysis of two phase III trials [AURA3 (NCT02151981), FLAURA (NCT02296125)]. All patients had EGFR mutation-positive (EGFRm; ex19del or L858R) advanced NSCLC; AURA3 also included T790M-positive NSCLC. Osimertinib (FLAURA, AURA3), or comparator EGFR-tyrosine kinase inhibitor (EGFR-TKI; gefitinib/erlotinib; FLAURA), or platinum-based doublet chemotherapy (AURA3) was given. Plasma EGFRm was analyzed at baseline and Weeks 3/6 by droplet digital PCR. Outcomes were assessed by detectable/non-detectable baseline plasma EGFRm and plasma EGFRm clearance (non-detection) at Weeks 3/6.In AURA3 (n = 291), non-detectable versus detectable baseline plasma EGFRm had longer median progression-free survival [mPFS; HR, 0.48; 95% confidence interval (CI), 0.33-0.68; P < 0.0001]. In patients with Week 3 clearance versus non-clearance (n = 184), respectively, mPFS (months; 95% CI) was 10.9 (8.3-12.6) versus 5.7 (4.1-9.7) with osimertinib and 6.2 (4.0-9.7) versus 4.2 (4.0-5.1) with platinum-pemetrexed. In FLAURA (n = 499), mPFS was longer with non-detectable versus detectable baseline plasma EGFRm (HR, 0.54; 95% CI, 0.41-0.70; P < 0.0001). For Week 3 clearance versus non-clearance (n = 334), respectively, mPFS was 19.8 (15.1 to not calculable) versus 11.3 (9.5-16.5) with osimertinib and 10.8 (9.7-11.1) versus 7.0 (5.6-8.3) with comparator EGFR-TKI. Similar outcomes were observed by Week 6 clearance/non-clearance.Plasma EGFRm analysis as early as 3 weeks on-treatment has the potential to predict outcomes in EGFRm advanced NSCLC.
Impaired Myocardial Calcium Uptake in Patients With Diabetes Mellitus
Authors: Abhishek Dattani, Shruti Joshi, Jian L. Yeo, Anvesha Singh, Emer M. Brady, Kelly S. Parke, Jayanth R. Arnold, Trisha Singh, Lucy E. Kershaw, Nicholas B. Spath, Rebecca M. Reynolds, Shareen Forbes, Fraser W. Gibb, Scott I. Semple, Marc R. Dweck, David E. Newby, Gerry P. McCann, Gaurav S. Gulsin
Journal: JACC. Cardiovascular imaging (2023)
Racial and Ethnic Disparities in Ambulatory Heart Failure Ventricular Assist Device Implantation and Survival
Authors: Debra D. Dixon, Shannon M. Knapp, Onyedika Ilonze, Sabra C. Lewsey, Sula Mazimba, Selma Mohammed, Harriette G.C. Van Spall, Khadijah Breathett
Journal: JACC Heart Failure (2023)
Evolution of Symptoms After Ustekinumab Induction Therapy in Patients With Crohn’s Disease
Authors: Jean-Frédéric Colombel, Bruce E. Sands, Christopher Gasink, Benjamin Yeager, Omoniyi J. Adedokun, James Izanec, Tony Ma, Long-Long Gao, Scott D. Lee, Stephan R. Targan, Subrata Ghosh, Stephen B. Hanauer, William J. Sandborn
Journal: Clinical Gastroenterology and Hepatology (2023)

Ustekinumab is an effective treatment of Crohn's disease (CD). Of interest to patients is knowing how soon symptoms may improve. We analyzed ustekinumab response dynamics from the ustekinumab CD trials.
Immunosuppressive nanoparticles containing recombinant PD-L1 and methotrexate alleviate multi-organ inflammation
Authors: Eun-Koung An, Wei Zhang, Hae-Bin Park, So-Jung Kim, Hee-Yun Eom, Juyoung Hwang, Minseok Kwak, Ji Yeon Lee, Peter Chang-Whan Lee, Jun-O Jin
Journal: Biomaterials (2023)
Durvalumab in Combination With Olaparib Versus Durvalumab Alone as Maintenance Therapy in Metastatic NSCLC: The Phase 2 ORION Study
Authors: Myung-Ju Ahn, Igor Bondarenko, Ewa Kalinka, Byoung Chul Cho, Shunichi Sugawara, Gabriella Gálffy, Byoung Yong Shim, Nikolay Kislov, Rajnish Nagarkar, Ingel Demedts, Steven J.M. Gans, Dolores Mendoza Oliva, Ross Stewart, Zhongwu Lai, Helen Mann, Xiaojin Shi, Maen Hussein
Journal: Journal of Thoracic Oncology (2023)

Increased DNA damage triggered through poly (ADP-ribose) polymerase inhibition may modify tumor immunogenicity, sensitizing tumors to immunotherapy. ORION (NCT03775486) evaluated the combination of olaparib with durvalumab as maintenance therapy in patients with metastatic NSCLC.ORION is a phase 2, randomized, multicenter, double-blind, international study. Patients with metastatic NSCLC (without activating EGFR or ALK aberrations) and Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled to receive initial therapy with durvalumab (1500 mg intravenously; every 3 wk) plus platinum-based chemotherapy for four cycles. Patients without disease progression were then randomized (1:1) to maintenance durvalumab (1500 mg; every 4 wk) plus either olaparib (300 mg orally) or placebo (both twice daily); randomization was stratified by objective response during initial therapy and tumor histologic type. The primary end point was investigator-assessed progression-free survival (PFS) (Response Evaluation Criteria in Solid Tumors version 1.1).Between January 2019 and February 2020, 269 of 401 patients who received initial therapy were randomized. As of January 11, 2021 (median follow-up: 9.6 mo), median PFS was 7.2 months (95% confidence interval: 5.3-7.9) with durvalumab plus olaparib versus 5.3 months (3.7-5.8) with durvalumab plus placebo (hazard ratio = 0.76, 95% confidence interval: 0.57-1.02, p = 0.074). Safety findings were consistent with the known profiles of durvalumab and olaparib. Anemia was the most common adverse event (AE) with durvalumab plus olaparib (26.1% versus 8.2% with durvalumab plus placebo). The incidence of grade 3 or 4 AEs (34.3% versus 17.9%) and AEs leading to treatment discontinuation (10.4% versus 4.5%) was numerically higher with durvalumab plus olaparib versus durvalumab plus placebo.Maintenance therapy with durvalumab in combination with olaparib was not associated with a statistically significant improvement in PFS versus durvalumab alone, although numerical improvement was observed.
Impact of Geroscience on Therapeutic Strategies for Older Adults With Cardiovascular Disease
Authors: Daniel E. Forman, George A. Kuchel, John C. Newman, James L. Kirkland, Elena Volpi, George E. Taffet, Nir Barzilai, Ambarish Pandey, Dalane W. Kitzman, Peter Libby, Luigi Ferrucci
Journal: Journal of the American College of Cardiology (2023)
A prospective controlled, randomized clinical trial of kidney transplant recipients developed personalized tacrolimus dosing using model-based Bayesian Prediction
Authors: Nuria Lloberas, Josep M. Grinyó, Helena Colom, Anna Vidal-Alabró, Pere Fontova, Raul Rigo-Bonnin, Ariadna Padró, Oriol Bestard, Edoardo Melilli, Nuria Montero, Ana Coloma, Anna Manonelles, Maria Meneghini, Alex Favà, Joan Torras, Josep M. Cruzado
Journal: Kidney International (2023)
Impaired Seroconversion After Severe Acute Respiratory Syndrome Coronavirus 2 mRNA Vaccine in Patients With Thymic Epithelial Tumors
Authors: Erica Pietroluongo, Pietro De Placido, Marianna Tortora, Claudia Martinelli, Angela Viggiano, Maria Rosaria Saponaro, Aldo Caltavituro, Roberto Buonaiuto, Rocco Morra, Margaret Ottaviano, Vitantonio Del Deo, Gustavo Cernera, Monica Gelzo, Anna Maria Malfitano, Michele Francesco Di Tolla, Carmine De Angelis, Grazia Arpino, Daniela Terracciano, Roberto Bianco, Bianca Maria Veneziani, Pietro Formisano, Giuseppe Castaldo, Giovannella Palmieri, Sabino De Placido, Mario Giuliano
Journal: Journal of Thoracic Oncology (2023)
Kidney Measures and Risk of Incident Heart Failure Among Older Adults
Authors: Antonios Douros, Alice Schneider, Natalie Ebert, Anne-Katrin Fietz, Dörte Huscher, Martin K. Kuhlmann, Peter Martus, Nina Mielke, Markus van der Giet, Volker Wenning, Elke Schaeffner
Journal: JACC Heart Failure (2023)
Opioid analgesia for acute low back pain and neck pain (the OPAL trial): a randomised placebo-controlled trial
Authors: Caitlin M P Jones, Richard O Day, Bart W Koes, Jane Latimer, Chris G Maher, Andrew J McLachlan, Laurent Billot, Sana Shan, Chung-Wei Christine Lin, Hanan McLachlan, Melissa Webb, Melanie Hamilton, Harbeer Ahedi, Angie Barber, Wendy Mak, Stephanie Mathieson, Veronika Petrova, Severine Bompoint, Sana Shan, Bridin Murnion, Nicholas Buckley, Apo Demirkol, Paul Wrigley, Christopher Needs, Louise Brooks, Samuel Cantori, Paul Preisz, James Aitken, Sujata Allan, Michael Burke, Greg Cameron, Francisco Javier Valencia Cepeda, Christopher Davis, Jayasree Dullur, Joseph Emmanuel, Catherine Errey, Sabine Fieuw-Makaroff, Adam Gaudry, L Genua, Ian Longhurst, Kenneth McCroary, Diana Merhi, Tanya Nguyen, Zahra Rassoly Obayd, Michelle Penm, Sharan Pobbathi, William S Poh, Paul Schnitzler, Sabiha Shahnaz, Ven Tan, Danny Tang, Brian Tan, Win Kyaw Thu, Thrasivolous Triantopolous, Ramana Venkatesan, Wicky Chun Fai Wong, Shu Ching Yang
Journal: The Lancet (2023)
Development of an adaptive clinical web-based prediction tool for kidney replacement therapy in children with chronic kidney disease
Authors: Derek K. Ng, Matthew B. Matheson, George J. Schwartz, Frances M. Wang, Susan R. Mendley, Susan L. Furth, Bradley A. Warady, Sahar Fathallah-Shaykh, Anjali Nayak, Martin Turman, Tom Blydt-Hansen, Cynthia Wong, Steve Alexander, Ora Yadin, Elizabeth Ingulli, Robert Mak, Cheryl Sanchez-Kazi, Asha Moudgil, Samina Muneeruddin, Carolyn Abitbol, Marissa DeFrietas, Chryso Katsoufis, Wacharee Seeherunvong, Larry Greenbaum, Lyndsay Harshman, Priya Verghese, Sonia Krishnan, Amy Wilson, Stefan Kiessling, Margaret Murphy, Siddharth Shah, Janice Sullivan, Sushil Gupta, Samir El-Dahr, Stacy Drury, Nancy Rodig, Allison Dart, Meredith Atkinson, Arlene Gerson, Tej Matoo, Zubin Modi, Jason Thomas, Bradley Warady, Rebecca Johnson, Vikas Dharnidharka, Stephen Hooper, Susan Massengill, Liliana Gomez-Mendez, Matthew Hand, Joann Carlson, Craig Wong, Frederick Kaskel, Shlomo Shinnar, Jeffrey Saland, Marc Lande, George Schwartz, Anil Mongia, Donna Claes, Mark Mitsnefes, Katherine Dell, Hiren Patel, Pascale Lane, Rulan Parekh, Lisa Robinson, Amira Al-Uzri, Kelsey Richardson, Susan Furth, Larry Copelovitch, Elaine Ku, Joshua Samuels, Poyyapakkam Srivaths, Samhar Al-Akash, Davoud Mohtat, Victoria Norwood, Joseph Flynn, Cynthia Pan, Sharon Bartosh
Journal: Kidney International (2023)
Atypical Gardner's Syndrome with Proptosis as the Primary Symptom
Authors: Mingyu Ren, Ruimiao Li, Limin Liu
Journal: Ophthalmology (2023)

A 20-year-old woman presented with a 3-year history of progressive proptosis of the right eye (A). Her father had a history of multiple osteomas. Congenital hypertrophy of the retinal pigment epithelial was not found on retinal examination, except for retinal folds. Multiple well-circumscribed masses of high radiodensity (B-D), and multiple unerupted supernumerary teeth (C-D) were observed on computed tomography. Gardner's syndrome was diagnosed after these findings were assessed. The osteomas of the right ethmoidal sinus were removed due to the threat of the intraorbital structure. She was advised to follow up regularly to detect the colonic polyps and extra-intestinal tumors (Magnified version of Figure A-D is available online at www.aaojournal.org).
A Phase I study of Milademetan (DS3032b) in combination with low dose cytarabine with or without venetoclax in acute myeloid leukemia: Clinical safety, efficacy, and correlative analysis
Authors: Jayastu Senapati, Muharrem Muftuoglu, Jo Ishizawa, Hussein A. Abbas, Sanam Loghavi, Gautam Borthakur, Musa Yilmaz, Ghayas C. Issa, Samuel I. Dara, Mahesh Basyal, Li Li, Kiran Naqvi, Rasoul Pourebrahim, Elias J. Jabbour, Steven M. Kornblau, Nicholas J. Short, Naveen Pemmaraju, Guillermo Garcia-Manero, Farhad Ravandi, Joseph Khoury, Naval Daver, Hagop M. Kantarjian, Michael Andreeff, Courtney D. DiNardo
Journal: Blood Cancer Journal (2023)

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 axis and the interplay between pro/anti-apoptotic molecules to identify factors that determine response and resistance to therapy. Sixteen patients (14 R/R, 2 N/D treated secondary AML) at a median age of 70 years (range, 23-80 years) were treated in this trial. Two patients (13%) achieved an overall response (complete remission with incomplete hematological recovery). Median cycles on trial were 1 (range 1-7) and at a median follow-up of 11 months, no patients remained on active therapy. Gastrointestinal toxicity was significant and dose-limiting (50% of patients ≥ grade 3). Single-cell proteomic analysis of the leukemia compartment revealed therapy-induced proteomic alterations and potential mechanisms of adaptive response to the MDM2i combination. The response was associated with immune cell abundance and induced the proteomic profiles of leukemia cells to disrupt survival pathways and significantly reduced MCL1 and YTHDF2 to potentiate leukemic cell death. The combination of milademetan, LDAC±venetoclax led to only modest responses with recognizable gastrointestinal toxicity. Treatment-induced reduction of MCL1 and YTHDF2 in an immune-rich milieu correlate with treatment response.
B07 HIGH EXPRESSION OF NUCLEAR CEREBLON IS ASSOCIATED WITH LONGER SURVIVAL IN PATIENTS WITH MULTIPLE MYELOMA TREATED WITH IMIDS
Authors: R. Wester, M. van Duin, K.H. Lam, S.S. Couto, Y. Ren, M. Wang, T. Cupedo, B. van der Holt, H.B. Beverloo, A.L. Nigg, A. Thakurta, A.A. Waage, S. Zweegman, A. Broijl, P. Sonneveld
Journal: HemaSphere (2023)

Patients with multiple myeloma (MM) demonstrate variable outcomes with treatment. With increasing treatment options, predictive factors for response and outcome are relevant to inform treatment choices. Immunomodulating agents (IMiDs) represent the cornerstone of MM treatment and act through binding to Cereblon (CRBN), affecting downstream targets of this E3 ubiquitin ligase. We hypothesized differential expression of effector or target proteins from the CRBN pathway to predict outcome in patients treated with IMiDs. Bone marrow (BM) biopsies were obtained from 148 newly diagnosed, transplant non-eligible patients with MM. Per HOVON-87/NMSG-18 trial protocol, these patients were treated with thalidomide or lenalidomide combined with melphalan and prednisone followed by thalidomide/lenalidomide maintenance (i.e. MPT-T or MPR-R). Immunohistochemistry was performed for CRBN, its neosubstrates Ikaros and Aiolos and the downstream targets interferon regulatory factor 4 (IRF-4) and cellular myelocytomatosis oncogene (c-MYC). Patients with response of VGPR or better have higher nuclear CRBN expression compared to patients with PR or worse (≥VGPR: median CRBN H-score=185 (interquartile range (IQR), 147-211) vs ≤PR median CRBN H-score=159 (IQR 129-193); p=0.02). Higher nuclear CRBN expression was associated with a longer progression-free survival (PFS) and overall survival (OS). For PFS a hazard ratio (HR) of 0.53 was found (95% confidence interval (CI) =0.37-0.77; p<0.001); for OS: HR = 0.59 (95% CI=0.38-0.90; p=0.02). The association between CRBN and OS varied with IRF-4 levels. In patients with IRF-4 levels above the median, a hazard ratio of 0.22 was found (95% CI=0.10-0.49; p=0.0002); in contrast, patients with IRF-4 levels below the median, had a hazard ratio of 0.82 (95% CI=0.44-1.53; p=0.5). For Ikaros, Aiolos and c-MYC no correlation with survival was found, either alone or in combination with CRBN. In conclusion, higher expression of nuclear CRBN was associated with a superior PFS and OS upon MPT or MPR treatment. Levels of nuclear CRBN protein, possibly in combination with IRF-4, may represent a biomarker for predicting treatment outcome in patients treated with IMiDs.
Mosunetuzumab and lymphoma: latest updates from 2022 ASH annual meeting
Authors: Yang Cao, Emanuela C. Marcucci, Lihua E. Budde
Journal: Journal of Hematology & Oncology (2023)

Abstract Bispecific antibodies are emerging as a promising new immunotherapy modality and are actively being evaluated in clinical trials for patients with lymphoma. As the first BsAb to receive regulatory approval for lymphoma, mosunetuzumab, an antiCD20/anti-CD3 BsAb, is an exciting new option for patients with relapsed or refractory (R/R) follicular lymphoma. The approval was based on results from an international, multicenter, phase 2 trial in patients with relapsed or refractory (R/R) follicular lymphoma following at least 2 prior lines of systemic therapy. Mosunetuzumab demonstrated remarkable efficacy with an overall response rate of 80% and complete response rate of 60%. Here we provided an overview of the latest clinical data on mosunetuzumab in lymphoma presented at the 2022 ASH Annual Meeting.
Sternomastoid intermuscular approach has better postoperative cosmesis and less neck discomfort than linea alba cervicalis approach in hemithyroidectomy: a randomized clinical trial
Authors: Linghui Chen, Qiwen He, Hedi Tian, Qinsheng Zhu, Yibin Shen, Yun Fang, Feng Zhu, Lixian Zhu, Liang Chen, Jun Pan, Yehui Du, Xiaochuan Yan, Qijun Zhang, Xueyu Zhou, Wen Tian, Yijun Wu
Journal: International Journal of Surgery (2023)

Surgery is still the most important treatment method for thyroid cancer. The classic linea alba cervicalis approach caused obvious neck scarring. This study explored an alternative open operative approach with concealed incision for hemithyroidectomy, and demonstrated whether it was non-inferior to traditional approach in postoperative complications and operation efficiency.Patients ( n =220) from November 2019 to November 2020 willing to undergo hemithyroidectomy because of differentiated thyroid cancer were randomly divided into the sternocleidomastoid intermuscular approach (SMIA) group ( n =110), and the linea alba cervicalis approach (LACA) group ( n =110). The incidence of postoperative complications within 3 months and operation efficiency indicator R0 resection rate were recorded as primary endpoint, while scar apperance was assessed as secondary endpoint. The data were statistically analyzed.The baseline data of these two groups were comparable, with no significant difference ( P >0.05). As primary endpoint, R0 resection rate was 100% in both groups. In the 1-month follow-up period, the SMIA group had a lower score for neck discomfort compared with that of the LACA group (1.01±0.1648 vs. 0.5657±0.0976, P =0.0217). The SMIA group's scar had better results from the observer scar assessment compared to that of the LACA group as secondary endpoint. Within the 3-month follow-up, the total complications were calculated, and it was demonstrated that SMIA was non-inferior to traditional LACA operation ( P of non-inferiority=0.0048).Compared with LACA group, surgery through the SMIA is safe, effective, and has non-inferior postoperative complications. SMIA can be considered an alternative approach to classic LACA in hemithyroidectomy.
Lung Cancer Screening in Asia: An Expert Consensus Report
Authors: David Chi-Leung Lam, Chong-Kin Liam, Sita Andarini, Samina Park, Daniel S.W. Tan, Navneet Singh, Seung Hun Jang, Varut Vardhanabhuti, Antonio B. Ramos, Tomio Nakayama, Nguyen Viet Nhung, Kazuto Ashizawa, Yeun-Chung Chang, Jamsak Tscheikuna, Cong Cung Van, Wai Yee Chan, Yeur-Hur Lai, Pan-Chyr Yang
Journal: Journal of Thoracic Oncology (2023)
Beyond UPR: cell-specific roles of ER stress sensor IRE1α in kidney ischemic injury and transplant rejection
Authors: Longhui Qiu, Xin Zheng, Dinesh Jaishankar, Richard Green, Deyu Fang, Satish Nadig, Zheng Jenny Zhang
Journal: Kidney International (2023)

Kidney damage due to ischemia or rejection results in the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER) lumen, a condition known as "ER stress." Inositol-requiring enzyme 1α (IRE1α), the first ER stress sensor found, is a type I transmembrane protein with kinase and endoribonuclease activity. On activation, IRE1α nonconventionally splices an intron from unspliced X-box-binding protein 1 (XBP1) mRNA to produce XBP1s mRNA that encodes the transcription factor, XBP1s, for the expression of genes encoding proteins that mediate the unfolded protein response. The unfolded protein response promotes the functional fidelity of ER and is required for secretory cells to sustain protein folding and secretory capability. Prolonged ER stress can lead to apoptosis, which may result in detrimental repercussions to organ health and has been implicated in the pathogenesis and progression of kidney diseases. The IRE1α-XBP1 signaling acts as a major arm of unfolded protein response and is involved in regulating autophagy, cell differentiation, and cell death. IRE1α also interacts with activator protein-1 and nuclear factor-κB pathways to regulate inflammatory responses. Studies using transgenic mouse models highlight that the roles of IRE1α differ depending on cell type and disease setting. This review covers these cell-specific roles of IRE1α signaling and the potential for therapeutic targeting of this pathway in the context of ischemia and rejection affecting the kidneys.
Targeting galectin-3 in inflammatory and fibrotic diseases
Authors: Selena Bouffette, Iuliana Botez, Frédéric De Ceuninck
Journal: Trends in Pharmacological Sciences (2023)

Galectin (Gal)-3 is a β-galactoside-binding lectin emerging as a key player in cardiac, hepatic, renal, and pulmonary fibrosis and inflammation, respiratory infections caused by COVID-19, and neuroinflammatory disorders. Here, we review recent information highlighting Gal-3 as a relevant therapeutic target in these specific disease conditions. While a causal link was difficult to establish until now, we discuss how recent strategic breakthroughs allowed us to identify new-generation Gal-3 inhibitors with improved potency, selectivity, and bioavailability, and report their usefulness as valuable tools for proof-of-concept studies in various preclinical models of the aforementioned diseases, with emphasis on those actually in clinical stages. We also address critical views and suggestions intended to expand the therapeutic opportunities provided by this complex target.
Increased G3BP2-Tau interaction in tauopathies is a natural defense against Tau aggregation
Authors: Congwei Wang, Marco Terrigno, Juan Li, Tania Distler, Nikhil J. Pandya, Martin Ebeling, Stefka Tyanova, Jeroen J.M. Hoozemans, Anke A. Dijkstra, Luisa Fuchs, Shengqi Xiang, Azad Bonni, Fiona Grüninger, Ravi Jagasia
Journal: Neuron (2023)

Many RNA-binding proteins (RBPs), particularly those associated with RNA granules, promote pathological protein aggregation in neurodegenerative diseases. Here, we demonstrate that G3BP2, a core component of stress granules, directly interacts with Tau and inhibits Tau aggregation. In the human brain, the interaction of G3BP2 and Tau is dramatically increased in multiple tauopathies, and it is independent of neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). Surprisingly, Tau pathology is significantly elevated upon loss of G3BP2 in human neurons and brain organoids. Moreover, we found that G3BP2 masks the microtubule-binding region (MTBR) of Tau, thereby inhibiting Tau aggregation. Our study defines a novel role for RBPs as a line of defense against Tau aggregation in tauopathies.